Camptothecin and related analogues display unprecedented antitumor activities against a variety of human cancers. To date the full therapeutic utilities of these agents have been limited by the aqueous instability of their lactone ring moiety, with the intactness of this pharmacophore an essential requirement for antitumor activity. For each drug ring opening is rapid under physiological condiitons (i.el, pH 7.0 or above), resulting in a complete loss of biological activity. In recently completed investigations [Burke et al., Journal of the American Chemical Society 114:8318-8314, (1992); Burke et al., Biochemistry 32:5352-5364, (1993)], we have demonstrated that liposome-bound camptothecin drugs are stable. Liposome stability data presented herein suggest that liposomes may potentially serve as carriers of camptothecin drugs which conserve both lactone ring and enhance antitumor activities. The present proposal is a four-year study aimed at evaluating the cellular pharmacology, blood stability, antitumor activity, toxicity, pharmacokinetics, organ distribution and tumor uptake of several prototype liposomal preparations of newly-synthesized lipophilic camptothecins. Despite favorable findings over the past ten years indicating that the more lipophilic camptothecin analogues are the most potent compounds against experimental cancers including multidrug-resistant (MDR) phenotypes, their further development has been sidetracked due to formulation problems. However, our recent experiments clearly show that liposomal formulations result in both enhanced drug stability and marked improvements in antitumor activity. Such an approach allows the liposomes to both solubilize and stabilize the drugs. The concept of liposomal drug delivery is an intriguing one in that it opens the door to the further development and evaluation of lipophilic camptothecins such as 10,11- methylenedioxycamptothecin more potent and MDR-active than water-soluble analogues such as 9-aminocamptothecin, topotecan, and CPT-11. Liposome formulations stabilize and enhance the in vitro antitumor activities of camptothecins; thus they may be of potential utility for introducing this promising class of anticancer agents to cancer victims. We propose here to explore the feasibility of liposomes as drug delivery vehicles for lipophilic analogues.